The purpose of these studies is to continue to evaluate the toxic effects of MDMA and METH (Ecstasy) in SOD-Transgenic mice. The subacute and long-term biochemical effects of methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) were assessed in homozygous and heterozygous transgenic (Tg) mice that carry the complete sequence of the human copper-zinc (CuZn) superoxide dismutase (SOD) gene. Non-transgenic (NON-Tg) mice showed significant decreases in striatal dopamine (DA) and dihydroxyphenylacetic acid (50 mg/kg) after MDMA treatment. Heterozygous SOD-Tg mice showed DA depletion only at the 354 h time point. In contrast, homozygous SOD-Tg mice showed no DA or DOPAC depletion at either the 24 h or at the 2 week time points. METH injections caused marked depletion of dopamine terminals in wild- type mice. However, both heterozygous and homozygous SOD-Tg mice showed protection against the toxic effects of METH with the homozygous animals showing the greatest protection. These results support previous observations that MDMA-induces biochemical in the 5-HT systems of rats. The present observations also document a role for the production of superoxide radicals in the effects of both MDMA and METH. These mice are an important tool for dissecting pathways involved in drug-induced neurotoxicity.